TY  - JOUR
AU  - Ameratunga, R
AU  - Koopmans, W
AU  - Woon, S-T
AU  - Leung, E
AU  - Lehnert, K
AU  - Slade, CA
AU  - Tempany, JC
AU  - Enders, A
AU  - Steele, R
AU  - Browett, P
AU  - Hodgkin, PD
AU  - Bryant, VL
Y2  - 2020/12/21
Y1  - 2017/10/20
SN  - 2050-0068
UR  - http://hdl.handle.net/11343/257600
AB  - Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband.
LA  - English
PB  - WILEY
T1  - Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus
DO  - 10.1038/cti.2017.41
IS  - Clinical and Translational Immunology
VL  - 6
IS  - 10
L1  - /bitstream/handle/11343/257600/PMC5671988.pdf?sequence=1&isAllowed=y
ER  -